WO2007103528A2 - Granules résistants compressibles et formules élaborées à partir desdits granules - Google Patents

Granules résistants compressibles et formules élaborées à partir desdits granules Download PDF

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Publication number
WO2007103528A2
WO2007103528A2 PCT/US2007/005975 US2007005975W WO2007103528A2 WO 2007103528 A2 WO2007103528 A2 WO 2007103528A2 US 2007005975 W US2007005975 W US 2007005975W WO 2007103528 A2 WO2007103528 A2 WO 2007103528A2
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WO
WIPO (PCT)
Prior art keywords
granule
agents
granules
mpa
composition
Prior art date
Application number
PCT/US2007/005975
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English (en)
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WO2007103528A3 (fr
Inventor
S. Rao Cherukuri
Original Assignee
Capricorn Pharma, Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Capricorn Pharma, Inc filed Critical Capricorn Pharma, Inc
Priority to PCT/US2007/005975 priority Critical patent/WO2007103528A2/fr
Priority to PCT/US2007/019400 priority patent/WO2008111954A1/fr
Publication of WO2007103528A2 publication Critical patent/WO2007103528A2/fr
Publication of WO2007103528A3 publication Critical patent/WO2007103528A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the present invention relates generally to methods and compositions having resilient granules. Accordingly, the present invention involves the fields of chemistry, biology, and pharmaceuticals.
  • oral dosage forms such as tablets, caplets, capsules, sachets, powders, etc. can have a number of associated problems.
  • the oral dose form can be rather large due to the drug, carrier, and other excipients needed.
  • Such forms are commonly referred to as "horse-pills.”
  • Many patients refuse to take such "horse-pills” and try to cut or crush them into smaller sizes to facilitate easy swallowing.
  • the tablets break and do not provide uniformity in dosing, or because they lack the protective coating in the broken areas, the patient feels the bitter taste of a typical active agent. Neither is an acceptable choice for the patient.
  • a resilient self adhering granule can include a combination of a polysaccharide in an amount of about 10 wt% to about 30wt%; a sugar alcohol in an amount of about 15 wt% to about 35 wt%; and a binder having a viscosity from about 5000 mPa.s (milliPascals.s) to about 250,000 mPa.s, in an amount of about 10 wt% to about 35 wt%, that is capable of low-pressure, reversible agglomeration.
  • the granule can further include an active agent or nutritional material.
  • an oral dosage composition can comprise a plurality of resilient self adhering granules that have agglomerated to form an oral dosage form.
  • the oral dosage form can contain a plurality of active agents in a single granule or active agents individually present in individual granules ' .
  • the oral dosage form can comprise a tablet that can be broken into two forms with substantially no material loss and can be reformed with substantially no material loss..
  • a method of administering an active agent to a subject can comprise providing the active agent in an oral dosage form comprising resilient self- adhering granules, and administering the oral dosage form to the subject's oral cavity such that the majority of the active agent is released in the gastrointestinal tract at a point after the mouth.
  • the active agent can be present in the resilient self-adhering granule or a non-resilient granule.
  • the oral dosage form in some aspects is not a chewing gum and does not use chewing gum base.
  • resilient refers to the ability of a material to retain its general characteristics and/or individuality even though acted upon by an outside force. For example, granules that are resilient may retain many or most of their individual characteristics, such as internal structure, crystallinity, melting point, etc., even when acted upon by mild to moderate external pressures.
  • the phrase "self-adhering” refers to a granule's ability to agglomerate with other like granules or particles under various pressures.
  • the term “free-flowing” refers to the ability to not agglomerate under atmospheric pressure or otherwise to not substantially adhere to objects of a different material.
  • the term "agglomeration” refers to a cluster of like particles in which the particles are held together by surface forces.
  • low-pressure, reversible agglomeration refers to granules that agglomerate with low pressure, typically about 6500 kilonewtons/m 2 , and that yet retain their individuality to a degree sufficient to allow easy delamination of particles from the agglomerate which are substantially intact with their original individual properties. In some cases, such granules may not substantially rupture or break upon delamination from the agglomerate.
  • sugar alcohol refers to a hydrogenated form of carbohydrate, whose carbonyl group (aldehyde or ketone, reducing sugar) has been reduced to a primary or secondary hydroxyl group. This term is also commonly known as polyol, polyhydric alcohol, or polyalcohol.
  • Sugar alcohols include, but are not limited to, arabitol, erythritol, hydrogenated starch hydrolysates, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, galactitol, inositol, ribitol, dithioerythritol, dithiothreitol, glycerol, and mixtures thereof.
  • Carbohydrate refers to molecules having straight-chain aldehydes or ketones with many hydroxyl groups added, usually one on each carbon atom that is not part of the aldehyde or ketone functional group. Carbohydrates include monosaccharides, disaccharides, oligosaccharides and polysaccharides. Carbohydrates are the most abundant biological molecules, and fill numerous roles in living things, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals).
  • Basic carbohydrate units are called monosaccharides, e.g., glucose, galactose, and fructose.
  • the general chemical formula of an unmodified monosaccharide is (C-H 2 O) n , where n is any number of three or greater.
  • Monosaccharides can be linked together in almost limitless ways. Two joined monosaccharides are called disaccharides, e.g., sucrose and lactose.
  • Carbohydrates containing between about three to six monosaccharide units are termed oligosaccharides; anything larger than this is a polysaccharide.
  • Polysaccharides, such, as starch, glycogen, or cellulose can reach many thousands of units in length.
  • Polysaccharides include, but are not limited to, simple sugars, complex sugars, fibers, starches, pectins, dextrans, dextrins, natural gums, synthetic gums, mucilages, derivatives thereof, components thereof, and mixtures thereof.
  • the term “dextrin” refers to low-molecular-weight carbohydrates produced by the hydrolysis of starch.
  • Dextrins are mixtures of linear ⁇ -(l,4)-linked D- glucose polymers. Generally, dextrins are water soluble, white to slightly yellow solids which are optically active. The term dextrin includes maltodextrins.
  • maltodextrin refers to partially hydrolysated starches. Maltodextrins are defined by the FDA as products having a dextrose equivalent (DE) less than 20. Starch hydrolysates are generally produced by heat, acid, or enzymes. This process breaks down the starch and converts some of the starch to dextrose. With adjustments, this process yields more or less dextrose. Maltodextrins are therefore classified by dextrose equivalence. Dextrose equivalents are a measure of the reducing sugars present calculated as dextrose and expressed as a percentage of the total dry substance. Maltodextrins can have a dextrose equivalent of up to 20. At above 20 DE, the product is then generally classified as corn syrup solids, which are completely soluble and impart significant sweetness.
  • DE dextrose equivalent
  • the term “substantially” or “substantial” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
  • the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result.
  • compositions that is "substantially free of particles would either completely lack particles, or so nearly completely lack particles that the effect would be the same as if it completely lacked particles.
  • a composition that is "substantially free of an ingredient or element may still contain such an item as long as there is no measurable effect thereof.
  • the term "about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be "a little above” or "a little below” the endpoint.
  • the present invention provides resilient, self-adhering granules that are capable of low-pressure, reversible agglomeration. For example, when the present granules are pressed between one's thumb and index finger, the granules agglomerate to form a resilient mass, which does not substantially stick to the fingers but rolls freely and can assume any shape desired. Therefore, the granules can be termed free-flowing as well as resilient and compressible.
  • the granules of the present invention are elastic in nature.
  • the plasticity of the granules may arise from their unique internal structure. This is to be contrasted with compressible granules known in the art which are used to form traditional tablets or traditional chewable tablets or orally disintegrating tablets.
  • the granules of the art do not agglomerate but rather typically are destructurized into smaller particles or powder when subjected to light pressure as described in this paragraph. These destructurized smaller particles or powder is an irreversible phenomenon and cannot be re-formed into granules that are substantially of original shape and size unless a very high compression force or some other formulation technique is used.
  • dosage forms such as tablets and caplets made from present granules are resistant to breakage or chipping. Further, if a patient breaks the tablet or caplet either intentionally to reduce dosage size or by accident, the dosage form can be easily reconstructed to its original shape and mass without any substantial loss of material and with minimal visibly distinct breakage mark. The tablet or caplet can be easily reconstructed to its original shape simply by holding the pieces opposite to each other and by applying light pressure in opposite directions. The pieces simply bond or agglomerate together. This should be contrasted with the art-known dosage forms made from art- known granules wherein the dosage form cannot be reconstructed ordinarily under light pressure.
  • a traditional art-known tablet with 500mg or more of active ingredient may become a so-called "horse-pill" when formulated with all needed excipients and can become unwieldy to a patient.
  • the present invention provides several advantages over such a dosage form: a) because of the compactness achieved by virtue of the unique internal structure of the resilient, self-adhering granules, the oral dosage forms produced therefrom do not become so big to be considered “horse-pill”; b) even if the dosage form is considered big for some patients, the breaking of the tablet or caplet is much more easily accomplished compared with traditional tablets; and c) since the granules have a relatively high moisture content, the tablet portions can easily and quickly glide in one's mouth with minimal residence time, which minimizes unpleasant taste of uncoated active drug.
  • the active drug can be taste-masked or coated. While the art-known granules may comprise coated or taste-masked active drug, for the reasons discussed above, because such granules lack the unique internal structure of the presently disclosed granules, the resulting product is not either compact, or difficult to break, or does not provide uniformity of dosing, or does not glide in the mouth as comfortably, or has a longer residence time in the mouth. In addition, because the art-known granules are not resilient, or as resilient as the granules of the present invention, the art-known granules, when presented to a patient in a rapidly disintegrating composition, brings out a powdery gritty mouth-feel to the patient. In contrast, the granules of the present invention create a smooth, pleasant mouth-feel. This is especially advantageous in case of pediatric or geriatric patients or patients who have a compromised saliva production (e.g., xerostemia patients or AIDS patients).
  • a compromised saliva production e.g.
  • the present invention provides methods and compositions directed to resilient, self-adhering granules. It is noted that when discussing a method of administering an oral dosage form comprising resilient, self-adhering granules or a composition of self-resilient granules, each of these discussions can be considered applicable to each of these embodiments, whether or not they are explicitly discussed in the context of that embodiment. Thus, for example, in discussing the binders present in a resilient, self-adhering granule, those binders can also be used in an oral dosage form comprising the granules or a method of administering such an oral dosage form, and vice versa.
  • resilient self-adhering granules can include a combination of a polysaccharide in an amount of about 10 wt% to about 30wt%; a sugar alcohol in an amount of about 15 wt% to about 35 wt%; and a binder having a viscosity from about 5,000 mPa.s to 250,000 mPa.s in an amount of about
  • the sugar alcohols can include, but are not limited to, arabitol, erythritol, hydrogenated starch hydrolysates, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, galactitol, inositol, ribitol, dithioerythritol, dithiothreitol, glycerol, derivatives thereof, and mixtures thereof.
  • the sugar alcohol can be maltitol.
  • the polysaccharides can include, but are not limited to, simple sugars, complex sugars, fibers, starches, pectins, dextrans, dextrins, natural gums, synthetic gums, mucilages, derivatives thereof, components thereof, and mixtures thereof.
  • the polysaccharide can be a dextrin.
  • the dextrin can be maltodextrin.
  • the resilient, self-adhering granules can be pharmaceutically acceptable.
  • Such pharmaceutically acceptable granules may be inert (i.e., comprise no pharmaceutically active agent) or may comprise one or more pharmaceutically active agents.
  • Pharmaceutical oral dosage forms such as tablets, caplets, capsules, sachets, powders and the like comprising compressible resilient granules of the present invention are also provided. Methods for making and using such granules and dosage forms are also provided.
  • the resilient, self-adhering granules of the present invention can be compressed into a tablet or a caplet of a desirable shape and size. Such compression can be achieved by using compression forces that are known in the pharmaceutical industry, such as those forces ranging from about 100 to about 4000 lbs/in 2 . However, the present granule can also agglomerate under low-pressure. Generally, such low pressure can be about 6500 kilonewtons/m 2 . Additionally, the granules of the present invention can withstand pressures of up to 40 kilonewtons of compression pressure without losing their resiliency.
  • the resilient, self-adhering granules of the present invention can have a moisture content ranging from about 0.1% to about 10%.
  • the moisture content can range from about 0.1% to about 6%, from about 0.5% to about 4%, from about 1% to about 4%, from about 1% to about 8%, from about 0.5% to about 7%, from about 3% to about 6%, or from about 0.5% to about 7%.
  • This moisture content is generally considered to be high for a compressible tablet.
  • the present compressible granules can be characterized as compressible granules of high moisture content.
  • the present granules can have a water activity less than about 0.6.
  • the water activity may be less than about 0.5, less than about 0.4, less than about 0.3, or less than about 0.2.
  • the water activity may range from about 0.1 to about 0.5, from about 0.1 to about 0.4, from about 0.1 to about 0.3, from about 0.1 to about 0.2, from about 0.2 to about 0.5, or from about 0.15 to about 0.5.
  • the compressible granules of the present invention can be combined in order form a variety of oral dosage formulations.
  • the granules may be compressed or agglomerated into a tablet or a caplet, and can be combined into semi-solid oral dosage formulations, granule filled capsules, and suspensions.
  • Those of ordinary skill in the art will appreciate the plethora of possible end formulations that can be created by combining together the resilient granules described herein.
  • tablet and caplets nearly any shape or size can be employed.
  • the tablets and caplets thus formed can be, for example, round, oval, square, rectangular, cylindrical, oblong, triangular, octagonal, hexagonal, and the like.
  • the tablets and caplets may be scored to provide dosing flexibility.
  • the tablets can be scored to permit two half dosings, or three one-third dosings (i.e., scored twice), or four one-quarter dosings.
  • Other shapes and scoring configurations are also feasible.
  • semi-solid oral formulations such formulations are typically soft and chewable and once broken up in the mouth through mastication are then swallowed in order to administer any included active agent to the subject at a point in the gastrointestinal tract which is past, or beyond, the mouth. It is understood that semi-solid formulations expressly excludes chewing gum, which are by contrast, meant to be chewed for a period of time and then spit out and not swallowed.
  • the unique internal structure of the present granules can permit dosage forms such as tablets or caplets that can be compact, i.e., have a high drug loading per surface area. Because of this unique characteristic of compactness, the present granules can be used to prepare oral dosage forms such as tablets or caplets that carry a high drug loading and yet permit easy swallowing without creating the fear of choking.
  • the compactness of the present dosage forms may be measured as a function of drug loading versus surface area, i.e., mg/cm 2 . In one aspect, the compactness can be expressed as 0.05, 0.08, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7 in mg/cm 2 .
  • the compactness of present granules may be expressed as ranging from 0.01 to 0.5, 0.01 to 0.1, 0.01 to 0.2, or 0.01 to 0.3, in mg/cm 2 . In another aspect, the compactness may range from 0.05 to 0.1, 0.05 to 0.2, 0.05 to 0.3, 0.05 to 0.4, in mg/cm 2 . In another aspect, the compactness may range from 0.1 to 0.2, 0.1 to 0.3, 0.1 to 0.4, or 0.1 to 0.5, in mg/cm 2 .
  • the compressible granules of the present invention despite its high moisture content, can be free-flowing and may not substantially stick to metal surfaces such as punches and dies and processing equipment such as granulators, dryers, mixers, coaters, etc.
  • This attribute. can permit high volume manufacture of tablets, caplets, capsules, powders, sachets, etc., offering significant commercial advantage. It should be mentioned that it is the prevailing understanding in the industry that high moisture content in granules causes several difficulties in pharmaceutical formulations, and is thus actively discouraged.
  • granules are traditionally dried to have a moisture content of 0.1% or even much less to facilitate free- flow of granules, which is an essential requirement for achieving high-speed high- volume tabletting to meet commercial production demands. Further, it is generally considered that high moisture content is detrimental to acceptable stability of the formulations.
  • the present invention has uniquely provided stable, free-flowing compressible granules that are highly desirable both from a consumer point-of-view and from industry point-of-view.
  • the resilient, self-adhering granules of the present invention can comprise a binder or a mixture of binders wherein at least one of the binders can have a viscosity of at least about 5,000 mPa.s. In some aspects, the viscosity of the binder can be greater than about 6,000 mPa.s.
  • the viscosity of the binder can be greater than about 7,000 mPa.s, about 8,000 mPa.s, about 10,000 mPa.s, about 12,000 mPa.s, about 14,000 mPa.s, about 16,000 mPa.s, about 18,000 mPa.s, about 20,000 mPa.s, about 22,000 mPa.s, about 24,000 mPa.s, about 26,000 mPa.s, about 28,000 mPa.s, about 30,000 mPa.s, about 60,000 mPa.s, about 80,000 mPa.s, about 100,000 mPa.s, about 120,000 mPa.s, about 150,000 mPa.s, about 180,000 mPa.s, about 210,000 mPa.s, and about 240,000 mPa.s.
  • the viscosity of at least one of the binders can range from about 5,000 mPa.s to about 250,000 mPa.s, from about 5,000 mPa.s to about 200,000 mPa.s, from about 5,000 mPa.s to about 180,000 mPa.s, from about 5,000 mPa.s to about 150,000 mPa.s, from about 5,000 mPa.s to about 130,000 mPa.s, from about 5,000 mPa.s to about 100,000 mPa.s, from about 5,000 mPa.s to about 80,000 mPa.s, from about 5,000 mPa.s to about 60,000 mPa.s, from about 5000 mPa.s to about 50,000 mPa.s, from about 5000 mPa.s to about 40,000 mPa.s, from about 5000 mPa.s to about 30,000 mPa.s, from about 5,000 mPa
  • the viscosity of at least one of the binders can range from about 7,000 mPa.s to about 30,000 mPa.s, from about 7,000 mPa.s to about 25,000 mPa.s, from about 7,000 mPa.s to about 20,000 mPa.s, from about 7,000 mPa.s to about 15,000 mPa.s, from about 7,000 mPa.s to about 13,000 mPa.s, and from about 7,000 mPa.s to about
  • the viscosity of at least one of the binders can range from about 10,000 mPa.s to about 30,000 mPa.s, from about 10,000 mPa.s to about 25,000 mPa.s, from about 10,000 mPa.s to about 20,000 mPa.s, from about 10,000 mPa.s to about 15,000 mPa.s, and from about 10,000 mPa.s to about 13,000 mPa.s, from about 10,000 mPa.s to about 250,000 mPa.s, from about 10,000 mPa.s to about 200,000 mPa.s, from about 10,000 mPa.s to about 180,000 mPa.s, from about 10,000 mPa.s to about 150,000 mPa.s, from about 10,000 mPa.s to about 120,000 mPa.s, from about 10,000 mPa.s to about 100,000 mPa.s, from about 10,000 mPa.s to about 80,000 m
  • the viscosity of at least one of the binders can range from about 8,000 mPa.s to about 250,000 mPa.s, from about 8,000 mPa.s to about 200,000 mPa.s, from about 8,000 mPa.s to about 150,000 mPa.s, from about 8,000 mPa.s to about 100,000 mPa.s, from about 8,000 mPa.s to about 80,000 mPa.s, and from about 8,000 mPa.s to about 50,000 mPa.s.
  • the viscosity of at least one of the binders can range from about 10,000 mPa.s to about 28,000 mPa.s, from about 10,000 mPa.s to about 23,000 mPa.s, from about 10,000 mPa.s to about 18,000 mPa.s, from about 10,000 mPa.s to about 14,000 mPa.s, and from about 10,000 mPa.s to about 13,000 mPa.s. It should be understood that a mixture of binders may be used in the present invention such that the binders in combination may possess a viscosity as recited in the previous paragraphs.
  • a binder such as Lycasin (maltitol syrup) of a lower viscosity (e.g., 2,000 mPa.s) may be combined in different proportions with another binder of higher viscosity (e.g., Lycasin HBC, maltitol syrup of 13,000 rnPa.s or Lycasin HDS maltitol syrup with a viscosity of about 250,000 mPa.s) to provide an overall viscosity for the binder mixture of at least 5,000 mPa.s, or other viscosities recited hereinabove.
  • Lycasin HBC maltitol syrup of 13,000 rnPa.s
  • Lycasin HDS maltitol syrup with a viscosity of about 250,000 mPa.s
  • viscosities stated herein are those stated in the literature for the particular product as mentioned by the manufacturer of the product or in the reference books such as Handbook of Excipients or other equivalent source. In some cases, the viscosities are measured at a certain temperature, for example at 20 0 C or 30 0 C.
  • a certain temperature for example at 20 0 C or 30 0 C.
  • viscosity is often a function of temperature over a certain range of temperatures for most products.
  • Lycasin HDS is a maltitol syrup manufactured by Roquette America, Inc. The manufacturer states that Lycasin HDS has a viscosity of about 250,000 mPa.s at 30 0 C.
  • binders examples include: syrups such as maltitol syrups of varying viscosities; emulsifiers that can function as binders; fats and waxes that can function as binders; and gums that function as binders.
  • emulsifiers examples include, but are not limited to, acetylated mono, di, or triglycerides or other esters; or polyethyleneglycol esters. Additionally, plasticizers may also be used.
  • fats and waxes that function as binders include, but are not limited to, bees wax, carnuba wax, spermaceti, etc.
  • Synthetic waxes include, but are not limited to, mineral oil, paraffin, microcrystalline wax, and polyethylene wax.
  • examples of gums that function as binders include, but are not limited to, gum Arabica, gum tragacanth, gum acacia, and fiber gums.
  • the binder can be a maltitol syrup.
  • the compressible resilient granules of the present invention may be inert, i.e., do not comprise a pharmaceutically active agent, or may comprise one or more pharmaceutically active agents.
  • the active agent may be present homogenously throughout the granule or coated on the surface of the granule.
  • the granules may be used to prepare oral dosage forms such as tablets, caplets, capsules, sachets, powders and the like.
  • the compressible resilient granules are inert
  • the granules may be used to provide sufficient flexibility for other ingredients in the dosage form, including other granules, be they art-known granules that are not resilient or be they resilient granules of this invention, so that such ingredients can be compressed into a tablet or caplet or such ingredients can be compressed into a mass of material that can be filled into a capsule.
  • the resilient, self-adhering granules of the invention can be inert and mixed with art-known non-resilient granules which can comprise a pharmaceutically active agent and, for example, coated with a taste-masking coating material or a modified release coating material.
  • non-resilient granules which can comprise a pharmaceutically active agent and, for example, coated with a taste-masking coating material or a modified release coating material.
  • These two types of granules can be compressed into a dosage form such as a tablet or a caplet where there is no substantial breakage or loss of coating on the non-resilient granules. This is a significant advancement in the pharmaceutical arts because the problem of breakage of the coating of coated granules during compression is a well-known problem in the art.
  • enteric coated granules are not generally compressed for the fear that the enteric coating will break under the compression forces generally employed in pharmaceutical tabletting, and thus, cause premature leakage of the active drug in the stomach, before the drug reaches its intended target, namely, the intestines.
  • . taste-masked granules are generally known to rupture during compression, causing the drug to dissolve in the mouth while swallowing and thus creating a bitter unpleasant taste for the patient.
  • the present invention provides oral dosage compositions that provide an active agent to a subject in the gastrointestinal tract at a point after the mouth.
  • the compositions and methods of the present method can be considered comestible as defined herein.
  • the non-resilient art-known granules and the resilient granules of the present invention may both comprise a pharmaceutically active agent.
  • the active agent can be the same or in some aspects, the active agent can be different in each granule type.
  • the dosage of the active agent in each case may be the same or different.
  • the non-resilient granules may be coated to provide modified release for the active agent while the resilient granules of the invention provide an immediate delivery of the active agent.
  • different active agents may be present a single granule or individually present in individual granules. Also, a combination of these granules maybe present as immediate release, controlled release, or mixtures thereof.
  • a variety of dosage and release characteristics can be obtained by following the concepts and examples presented herein.
  • the unique characteristics of the present granules permit incorporation of a wide variety of active ingredients, regardless of their aqueous solubility or particle size.
  • active ingredients regardless of their aqueous solubility or particle size.
  • highly water soluble, sparingly water soluble, and water insoluble actives can be employed.
  • Particle sizes of the actives could range from about 50nm to about 500 uM.
  • nanoparticles and microprticles can be used to make the present resilient, self- adhering granules.
  • the active agents for example can include, but are not limited to, analgesics, anti- inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, anti epileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphospho
  • active agents include, without limitation, antitussives; decongestants; alkaloids; laxatives; antacids; ion exchange resins; anti-cholesterolemics; antipyretics; analgesics including acetaminophen, aspirin, non-asteroidal anti-inflammatory drugs
  • NSAID NSAID and opioids
  • appetite suppressants appetite suppressants; expectorants; anti-anxiety agents; antiulcer agents; coronary dilators; cerebral dilators; peripheral vasodilators; anti-infectives; psycho-tropics; antimanics; stimulants; gastrointestinal agents; sedatives; anti-diarrheal preparations; anti-anginal drugs; vasodilators; vasoconstrictors; migraine treatments; tranquilizers; anti-psychotics; antitumor drugs; antithrombotic drugs; hypnotics; antiemetics; anti-nausants; anti-convulsants; neuromuscular drugs; hyper-and hypoglycemic spasmodics; uterine relaxants; antiobesity drugs; anabolic drugs; erythropoetic drugs; antiasthmatics; mucolytics; anti-uricemic drugs; and mixtures thereof.
  • the active agent is selected from the group consisting of: an analgesic, an antibiotic, a lipid regulating agent, an antihistaimine, an antineoplastic agent, and an antiviral agent.
  • nutritional active materials may be delivered using the resilient, self adhering granules of the present invention and include, without limitation, calcium- containing materials such as calcium carbonate, stannol esters, hydroxycitric acid, vitamins, minerals, herbals, spices, and mixtures thereof.
  • vitamins that are available as active ingredients include, without limitation, vitamin A (retinol), vitamin D (cholecalciferol), vitamin E group, vitamin K group (phylloquinones and menaquinones), thiamine, riboflavin, niacin, folic acid, cobalamins, biotin, vitamin C (ascorbic acid), and mixtures thereof.
  • vitamin A retinol
  • vitamin D cholesterolcalciferol
  • vitamin E group vitamin K group
  • thiamine riboflavin
  • niacin folic acid
  • cobalamins biotin
  • vitamin C ascorbic acid
  • USRDA United States' Department of Agriculture Recommended Daily Allowances
  • the nutritional material can be zinc or calcium.
  • compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, emulsifiers, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients.
  • excipients are well-known in the art.
  • Resilient, self-adhering granules of the invention can be prepared by a variety of granulation techniques known in the art.
  • granulation can be accomplished by granulating in a fluidized bed and admixture comprising an active agent and one or more pharmaceutically acceptable water-soluble or water-dispersible excipients, to form a granule.
  • granulation may be performed by using high shear granulation.
  • the resilient self-adhering granules of the invention can be formulated into several known oral dosage forms.
  • tablets can be prepared by pharmaceutical compression or molding techniques known in the art.
  • powders for administration can be prepared from the granules of the present invention or directly as granulated powders by any method known in the art.
  • methods include, but are not limited to, milling, fluid bed granulation, dry granulation, direct compression, spheronization, spray congealing, and spray-dying.
  • tabletting methods are provided in Remington: The Science and Practice of Pharmacy, 19th ed Vol. 11 (1995) (Mack Publishing Co., Pennsylvania); and Remington's Pharmaceutical Sciences, Chapter 89, pp. 1633-1658 (Mach Publishing Company, 1990), both of which are specifically incorporated by reference.
  • an active agent and at least one pharmaceutically acceptable water- soluble or water-dispersible excipient, and, optionally, other excipients are mixed to form a blend which is then directly compressed into tablets.
  • an active agent can be blended with tablet excipients using a V-blender or high-shear mixer to produce free- flowing compressible granules, which may be sieved for size uniformity. This may be followed by compression of the powder-granules using, for example, an automated press, or a single station press, or a high-speed tablet press.
  • the tablets may be further coated or uncoated. If coated, they may be sugar- coated or film-coated (to cover objectionable tastes or odors and to protect against oxidation) or coated with a release-modifying coating material such as an enteric coating.
  • the present invention also provides methods to produce resilient, self-adhering granules.
  • the method may comprise of the following steps: a) heating mixed fats and emulsifiers to about 120 to about 220F to obtain liquid consistency; b) adding carbohydrates to said liquid of step a), optionally heating to about 120 to about 180F; c) adding active agent, and optionally excipients selected from the group consisting of sweeteners, swelling agents, flavoring agents, binders, disintegrants, bulking agents, and mixtures thereof; d) adding a binding agent and optionally blending; e) lowering temperature of the composition formed in step d) to a temperature below room temperature; and f) subjecting said composition of step e) to size-reduction methods selected from the group consisting of: milling, shearing, sieving, or a combination thereof to obtain substantially uniform sized compressible resilient granules.
  • the method further comprises adding lubricants and other tabletting ingredients such as flavorants, sweeteners
  • the method comprises using cooling aids such as dry ice to prevent stickiness prior to the milling step.
  • the method comprises using a lubricant such as silicon dioxide in an amount greater than about 1.5% w/w of the composition.
  • the lubricant is greater than about 2% w/w of the composition.
  • the lubricant is greater than about 2.5% w/w of the composition.
  • the lubricant is greater than about 3% w/w of the composition.
  • the present invention also provides methods of administering an active agent to a subject including providing the active agent in an oral dosage form, said oral dosage form can comprise resilient self-adhering granules as previously discussed, administering the oral dosage form to the subject's oral cavity, such that the majority of the active agent can be released in the gastrointestinal tract at a point after the mouth.
  • the tablet can be administered by breaking the tablet into two portions approximately defined by a scoring, where the breaking results in substantially no material loss. Additionally, the tablet can be reformed with substantially no material loss.
  • the oral dosage form can be characterized as not a gum or chew formulation.
  • Example 1 Zinc Acetate and Zinc Gluconate comprising resilient granules
  • Zinc Acetate and Zinc Gluconate comprising resilient granules were prepared.
  • the combined amount of elemental zinc was approximately 37mg in the final compressed product.
  • the composition had the following ingredients: mono- and di- glyceride emulsifiers (Durem 117) (60 mg); Panalite 90 DK (maltitol syrup) (30 mg); polyethylene glycol 3350 (40 mg); partially hydrogenated soybean oil and cotton seed oil (Kaomel) (10 mg); acetylated mono- and di-glycerides (Myvacet) (50 mg); maltodextrin (Maltrin M-180) (171 mg); maltitol syrup (Lycasin HDS) (200 mg); methylcellulose
  • the fats and emulsifying agents were mixed together in a mixer and heated till the ingredients were melted. Maltitol syrup was then added to the molten fat and was mixed thoroughly. To this was added the active ingredient and mixed further for about 10 minutes. The molten and mixed mass was then extruded in an extruder and the ropes were collected into trays. The ropes then were allowed to condition at room temperature for about 6-8 hrs. The dried roped material was then milled to desired particle size. During milling, dry ice was used as needed to avoid sticking of the material. The material was then cooled in a freezer or was used directly to lubrication and compression.
  • the resilient material was sifted through an appropriate mesh for the desired particle size.
  • the sifted material was then lubricated in a mixer by using a lubricant or lubricant mixture.
  • the lubricant was a mixture of magnesium stearate and talc comprising about 2.5% w/w of the final composition; however, other lubricants may be used.
  • colloidal silicon dioxide may also be used in addition to the above mixture of lubricants. If used, colloidal silicon dioxide may comprise about 3% w/w of the final composition.
  • Sweeteners, flavors, and colorants as desired my then be added to the blending mixture. If used, sweeteners, flavors, and colorants may add up to about 5% w/w of the final composition.
  • the mixer was run at 40 rpm and the mixing was continued for 10 minutes.
  • the material was then frozen in a refrigerator for about 6 hrs prior to compression.
  • the resilient granules were then compressed into tablets.
  • the uncoated tablets comprising resilient granules were then coated in a coating pan using a coating mixture comprising Crystalac C and talc.
  • the coating composition amounted to about 5% w/w of the final composition.
  • Example 2 Zinc acetate comprising compressible resilient granules
  • Example 1 was followed to make compositions comprising zinc acetate as the active agent.
  • the composition comprises zinc acetate: 5.6% w/w.
  • Example 3 Sumatriptan comprising compressible resilient granules
  • the composition comprised 20.1% w/w of sumatriptan, 24.5% w/w of mixed fats and emulsifiers, 17% w/w of maltodextrin, 23% w/w of maltitol syrup, with the remaining to include flavors, sweeteners, swelling agents, coloring agents, and lubricating agents.
  • the sumatriptan employed is an encapsulated taste-masked formulation prepared by art-known processes such as resin-complexation, complex coacervation, polymer- coating, and wax-fat coating.
  • the sumatriptan formulation provides 1 OOmg per dosage form.
  • the process for granule preparation was as follows. Mixed fats and emulsifiers were heated to 180-190F to obtain liquid consistency.
  • Maltitol syrup was added to this liquid mixture and heating continued to about 150F.
  • the mixture was then transferred to a Sigma mixer using front blade at 60 RPM for about 1-3 minutes.
  • the taste-masked sumatriptan, sweeteners, and swelling agents were added to this mixture, and blending continued for a few more minutes at 60 RPM.
  • Maltodextrin and flavors were added to this mixture, and blending continued for further few minutes.
  • sumatriptan may be added at this stage.
  • the mixture was then cooled. This was followed by size reduction using multi-mill with knife blade forward and screened to obtain uniform granule size using a size 12 screen. Lubricants and other tabletting ingredients including a glidant were added to these granules and the mixture was blended for a few minutes.
  • Example 4 Sumatriptan comprising compressible resilient granules
  • Example 3 The process described in Example 3 was followed with the exception that sumatriptan was added at the lubrication stage.
  • Example 5 Uncoated Active Ingredient Comprising compressible resilient granules
  • Example of either 1 or 2 is followed except that the active agent is uncoated drug and the drug is loratadine.
  • the loratadine is present from about 5 mg to 20 mg.
  • the remaining ingredients of the composition are adjusted accordingly to take into consideration the total weight percentages to substantially remain the same as previously described.
  • Example 6 Compressible resilient granules mixed with coated modified release granules
  • the Example of either 1 or 2 is followed except that the resilient compressible granules are made with no active agent.
  • the compressible resilient granules are made, these are mixed with granules or powder comprising active ingredients that are coated with a delayed release coating.
  • Olanzapine composition that is coated with a delayed release coating is used as an example to deliver 20mg olanzapine per dosage form. Preparation of such delayed release coated olanzapine is known in the art.
  • Granules of delayed release coated olanzapine are then mixed with compressible resilient granules at the lubrication stage into the final blend and the mixture is then compressed into a tablet as described above.
  • the dosage form delivers modified release olanzapine.
  • Example 7 Compressible resilient granules mixed with coated modified release granules
  • the Example of 6 is followed except that the resilient compressible granules are made with olanzapine that is not coated. These compressible granules are then mixed with granules of delayed release coated olanzapine at the lubrication stage into the final blend and the mixture is then compressed into a tablet as described above.
  • the dosage form delivers an initial immediate release dose of olanzapine followed by delayed release olanzapine to produce therapeutic activity over a longer duration, preferably tor 6-8 hrs or even longer, if desired.
  • Example 8 Compressible resilient granules mixed with coated modified release granules of two different actives
  • the Example of either 1 or 2 is followed except that the resilient compressible granules are made with the active agent comprising amlodipine.
  • Amlodipine besylate can be used as an example to deliver 5mg.
  • Amoldipine may be encapsulated for taste- masking purposes if needed.
  • compressible resilient granules comprising atorvastatin calcium are made.
  • the atorvastatin granules are made to deliver 10, 20, 40, or 80mg per dosage form and optionally are coated for taste-masking purposes as needed.
  • These two compressible resilient granules are then mixed, at the lubrication stage into the final blend and the mixture is then compressed into a tablet as described above.
  • the dosage form delivers combination of both amlodipine and atorvastatin.
  • Example 9 Compressible resilient granules mixed with coated modified release granules of two different actives and different release rates
  • amlodipine or atorvastatin may be prepared as delayed-release granules while the other drug is prepared as compressible resilient granules.
  • the two types of granules are then mixed, at the lubrication stage into the final blend and the mixture is then compressed into a tablet as described above.
  • the dosage form delivers an immediate release of either amlodipine or atorvastatin while providing modified release delivery of the other active.

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Abstract

La présente invention concerne des méthodes et des formules incluant des granules auto-adhérents résistants. Dans l'un des modes d'application, un granule auto-adhérent résistant qui inclut une combinaison d'un polysaccharide à une teneur comprise entre environ 10 % en poids et environ 30 % en poids ; un alcool sucré à une teneur comprise entre environ 15 % en poids et environ 35 % en poids ; et un liant de viscosité comprise entre environ 5000 mPa.s et environ 250 000 mPa.s à une teneur comprise entre environ 10 % en poids et environ 35 % en poids, est capable de s'agglomérer de façon réversible à basse pression. D'autres modes d'application concernent une forme galénique orale de tels granules ainsi que des méthodes d'administration desdites formes.
PCT/US2007/005975 2006-03-07 2007-03-07 Granules résistants compressibles et formules élaborées à partir desdits granules WO2007103528A2 (fr)

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US20040014680A1 (en) * 2000-10-16 2004-01-22 Hiroaki Nakagami Medicinal compositions quickly disintegrating in the oral cavity and process for producing the same

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EP2061437A1 (fr) * 2006-08-24 2009-05-27 Hanall Pharmaceutical Co., Ltd. Composition pharmaceutique combinée à libération contrôlée comprenant de la dihydropyridine, des bloqueurs de canal calcium et des inhibiteurs de l'hgm-coa réductase
EP2061437A4 (fr) * 2006-08-24 2012-09-26 Hanall Biopharma Co Ltd Composition pharmaceutique combinée à libération contrôlée comprenant de la dihydropyridine, des bloqueurs de canal calcium et des inhibiteurs de l'hgm-coa réductase
WO2009067684A1 (fr) * 2007-11-21 2009-05-28 Capricorn Pharma Inc. Formulations de niacine à libération modifiée
WO2009140557A2 (fr) * 2008-05-14 2009-11-19 Capricorn Pharma, Inc. Formulations de toltérodine à libération modifiée
WO2009140557A3 (fr) * 2008-05-14 2010-01-07 Capricorn Pharma, Inc. Formulations de toltérodine à libération modifiée

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